Novel compounds are continually sought after to treat and prevent diseases and disorders. Pharmaceutical companies interested in owning new active molecules develop or purchase chemical compounds or libraries in order to screen their activity against a particular target, aiming at the identification of new industrially useful products.
Therefore, there is a market of customer companies for which the acquisition of novel chemical compounds, not already biologically explored, is a key issue. And for the companies whose core business is the design and preparation of chemical compounds or chemical libraries, their commercialization has a clear industrial interest.
Although many research groups work to find novel compounds to be used in the treatment of known or novel diseases, the number of active new chemical entities in the market doesn't grow in the same extension. Over the past few years, there has been a progressive reduction in the number of medicines entering the market mainly due to the more stringent regulatory requirements that have raised the bar on safety and efficacy of new drugs.
The compounds described in this invention are useful for contributing to the exploration of the chemical space, for incrementing the structural diversity of valuable molecules in the pharmaceutical sector and for incrementing the elements of structural recognition in order to study their interaction with or modulation of targets of pharmaceutical or medicinal chemistry interest. For instance, the molecules may be therapeutically useful as anti-inflammatory or anticoagulation agents, among many other applications.
Compounds described in this invention are useful for being biologically and pharmaceutically explored, and therefore to contribute in the research and identification of new drug leads exhibiting the ability of target modulation, since these molecules are sources of chemical diversity not currently explored. The compounds of the present invention may be explored by means of any known method of biological screening. These methods comprise, but are not limited to, receptor affinity assays, ELISA assays, “southern”, “western” and “northern blot”, and competitive binding assays.
U.S. Pat. No. 7,126,006 B2 (The Scripps Research Institute) describes glycoluryl type molecules as scaffolds in the preparation of combinatorial libraries.
U.S. Pat. No. 6,939,973 B1 (The Scripps Research Institute) describes glycoluryl type molecules as scaffolds in the preparation of combinatorial libraries.
Smallheer et al. (Bioorganic & Medicinal Chemistry Letters (2008), 18(7), 2428-2433) disclose a series of sulfonamidolactams useful as coagulation Factor Xa inhibitors.
WO2004041776 (Bristol-Myers Squibb Company) discloses certain sulfonylamino-valerolactams that can be used as inhibitors of trypsin-like serine proteases, specifically factor Xa.
WO2002102380 (Bristol-Myers Squibb Pharma. Co.) discloses monocyclic and bicyclic carbocycles and heterocycles active as factor Xa inhibitors.
The search for novel drug lead compounds for drug discovery is a difficult task that has traditionally required the use of hundreds of thousands of compounds to reach a successful molecule, mainly due to the fact that drug discovery was driven by random screening and the chemical and biological intuition.
However, integrated approaches combining structural knowledge from conformationally constrained small peptides and parallel synthesis of small molecules are particularly well suited for the shortening of the time-consuming drug discovery process.
Compounds of formula (I) have been designed using computational techniques such as virtual library screening based on pharmacophore search. Virtual (database) screening (VS) is an important component of the computer-based search of novel lead compounds. The primary VS premise is to screen a database of molecules computationally using structural descriptors that relate in some way to potential biological activity. A subset of database molecules found to match these descriptors can then be selected for subsequent biological analysis. In terms of novel lead discovery, pharmacophore searching is one of the most widely applied VS methods.
Compounds of formula (I) are not an arbitrary selection of a vast amount of molecules. On the contrary, they have been designed using as starting point a pharmacophore for at least BK antagonism. In this context, a pharmacophore is defined as a critical arrangement of molecular fragments or features creating a necessary, although not sufficient, condition for biological activity and receptor affinity.
In order to improve the success of molecular bioactive conformations, applicants have defined the structure of compounds of formula (I) using a pharmacophore based on Hoe 140, the most potent peptide antagonist of brakykinin (BK, sequence: D-Arg0-Arg1-Pro2-Hyp3-Gly4-Thi5-Ser6-D-Tic7-Oic8-Arg9 (Hyp, hydroxyproline; Thi, β-(2-thienyl)-alanine; Tic, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; Oic, (2S,3aS,7aS)-octahydroindole-2-carboxylic acid). The pharmacophore for BK antagonism has been obtained from a conformational search using an iterative simulated annealing procedure. Corcho, F J. Computational Studies on the Structure and Dynamics of Bioactive Peptides, PhD Thesis, 2004.
In conclusion, all compounds of formula (I) exhibit at least Hoe 140 pharmacophore fulfillment, and therefore they share specific characteristics for receptor affinity critical in the search of novel bioactive molecules.